2 research outputs found
Nonclassical Size Dependence of Permeation Defines Bounds for Passive Adsorption of Large Drug Molecules
Macrocyclic peptides are considered
large enough to inhibit “undruggable” targets, but the
design of passively cell-permeable molecules in this space remains
a challenge due to the poorly understood role of molecular size on
passive membrane permeability. Using split-pool combinatorial synthesis,
we constructed a library of cyclic, per-N-methlyated peptides spanning
a wide range of calculated lipohilicities (0 < <i>A</i>log<i>P</i> < 8) and molecular weights (∼800
Da < MW < ∼1200 Da). Analysis by the parallel artificial
membrane permeability assay revealed a steep drop-off in apparent
passive permeability with increasing size in stark disagreement with
current permeation models. This observation, corroborated by a set
of natural products, helps define criteria for achieving permeability
in larger molecular size regimes and suggests an operational cutoff,
beyond which passive permeability is constrained by a sharply increasing
penalty on membrane permeation
Nonclassical Size Dependence of Permeation Defines Bounds for Passive Adsorption of Large Drug Molecules
Macrocyclic peptides are considered
large enough to inhibit “undruggable” targets, but the
design of passively cell-permeable molecules in this space remains
a challenge due to the poorly understood role of molecular size on
passive membrane permeability. Using split-pool combinatorial synthesis,
we constructed a library of cyclic, per-N-methlyated peptides spanning
a wide range of calculated lipohilicities (0 < <i>A</i>log<i>P</i> < 8) and molecular weights (∼800
Da < MW < ∼1200 Da). Analysis by the parallel artificial
membrane permeability assay revealed a steep drop-off in apparent
passive permeability with increasing size in stark disagreement with
current permeation models. This observation, corroborated by a set
of natural products, helps define criteria for achieving permeability
in larger molecular size regimes and suggests an operational cutoff,
beyond which passive permeability is constrained by a sharply increasing
penalty on membrane permeation